Unlike other tissues which can survive extended periods of hypoxia, brain tissue is particularly sensitive to deprivation of oxygen or energy. Permanent damage to neurons can occur during brief periods of hypoxia, anoxia or ischemia. Neurotoxic injury is known to be caused or accelerated by certain excitatory amino acids (EAA) found naturally in the central nervous system (CNS). Glutamate (Glu) is an endogenous amino acid which has been characterized as a fast excitatory transmitter in the mammalian brain. Glutamate is also known as a powerful neurotoxin capable of killing CNS neurons under certain pathological conditions which accompany stroke and cardiac arrest. Normal glutamate concentrations are maintained within brain tissue by energy-consuming transport systems. Under low energy conditions which occur during conditions of hypoglycemia, hypoxia or ischemia, cells can release glutamate. Under such low energy conditions the cell is not able to take glutamate back into the cell. Initial glutamate release stimulates further release of glutamate which results in an extracellular glutamate accumulation and a cascade of neurotoxic injury.
It has been shown that the sensitivity of central neurons to hypoxia and ischemia can be reduced by either blockage of synaptic transmission or by the specific antagonism of postsynaptic glutamate receptors [see S. M. Rothman and J. W. Olney, "Glutamate and the Pathophysiology of Hypoxia-Ischemic Brain Damage," Annals of Neurology, Vol. 19, No. 2 (1986)]. Glutamate is characterized as a broad spectrum agonist having activity at three neuronal excitatory amino acid receptor sites. These receptor sites are named after the amino acids which selectively excite them, namely: Kainate (KA), N-methyl-D-aspartate (NMDA or NMA) and quisqualate (QUIS).
Neurons which have EAA receptors on their dendritic or somal surfaces undergo acute excitotoxic degeneration when these receptors are excessively activated by glutamate. Thus, agents which selectively block or antagonize the action of glutamate at the EAA synaptic receptors of central neurons can prevent neurotoxic injury associated with hypoxia, anoxia, or ischemia caused by stroke, cardiac arrest or perinatal asphyxia.
It is known that glycine potentiates NMDA receptor-mediated responses. Also, there has been observed an allosteric interaction of glycine through a strychnineinsensitive glycine recognition site which is believed to form part of the NMDA receptor-ion channel complex [J. W. Johnson et al, Nature (London), 325, 529-531 (1987)]. For example, the compound 2-carboxy-4-hydroxyquinoline (also known as kynurenic acid) is a known NMDA antagonist and its NMDA antagonist activity can be reversed by the presence of glycine [G. B. Watson et al, Neurosci. Res. Comm., 2, No. 3, 169-174 (1988)]. Also, the compound 7chlorokynurenic acid has been shown to be an NMDA antagonist whose blocking effect can be reversed by glycine [I. A. Kemp et al, Proc. Natl. Acad. Sci. USA, 85 6547-6550 (1988)]. An excess of glycine may cause neuronal excitation and lead to overactivation of NMDA receptors which has been linked to seizure disorders and neurodegenerative disease [A. C. Foster et al, Nature, 388, 377-378 (1989)] .
Derivatives of indolecarboxylate compounds are known. For example, 2-carboxy-3-indoleacetic acid has been prepared from a hydrazone precursor [M. Passerini et al, Gazz. Chim. Ital., 69, 658-664 (1939)]. Similarly, the compounds 2-carboxy-5-chloro-3indoleacetic acid and ethyl 2-ethoxycarbonyl-3indoleacetic acid have been prepared from hydrazone precursors [V. V. Feofilaktov et al, Zhur. Obshchei Khim., 23, 644-656 (1953)]. Also, the compound 2-carboxy-3-indolepropionic acid has been prepared from the hydrazone precursor [L. Kalb et al, Chem. Ber. 59B, 1860-1870 (1926)]. The compounds 2-carboxy-3-indolebutyric acid and its ester, ethyl 2-carboxy-3-indolebutyrate, likewise have been prepared from hydrazone precursors [R. W. Jackson et al, J. Am. Chem. Soc., 52, 5029-5035 (1930); R. H. F. Manske et al, Can. J. Chem., 38, 620-621 (1960)].
Some indolecarboxylate compounds have been found to have agricultural-related utility. For example, Spanish Patent No. 195,444 describes ethyl 2-ethoxycarbonyl-3-indoleacetic acid as having phytohormonal activity. The compounds 5-bromo-2-carboxy-3-indoleacetic acid, 5-methyl-2-carboxy-3-indoleacetic acid and 7-chloro-2-carboxy-3-indoleacetic acid have been described as having auxin-like activity [O. L. Hoffmann et al, J. Biol. Chem., 196, 437-441 (1952)].
Other indolecarboxylate compounds and derivatives have been found to have pharmacological activity. For example, U.K. Patent No. 1,153,954 describes N-carbonyl/sulfonyl-3-indolylacetic acids as having antiinflammatory and antipyretic activity. Netherlands Patent No. 69-02641 describes N-carboxyalkyl-3-indoleacetic acid compounds as antiinflammatory and antipyretic agents.
Certain indole-2-carboxylate compounds lacking substitution on the indole nitrogen atom are known to have pharmacological activity. For example, Japanese Patent No. 69-8502 describes indoxylcarboxylic acid compounds having an unsubstituted indole nitrogen atom as antiinflammatory agents. Austrian Patent No. 352,708 describes 2-(alkoxycarbonyl)-3-indolealkanoic acid compounds having an unsubstituted indole nitrogen atom as antipyretic agents.